The aim of the proposed research is to define how genetic loss of MeCP2, the gene responsible for Rett Syndrome (Rett), disrupts Brain Derived Neurotrophic Factor (BDNF) signaling in autonomic reflex pathways in the brainstem nucleus tractus solitarius (nTS). nTS is the principal site at which visceral sensory input is integrated in the brainstem and defects in nTS function have been proposed to underlie autonomic dysfunctions in Rett. Normally, visceral sensory neurons, located in the nodose-petrosal cranial sensory ganglia (NPG), synthesize and release high levels of BDNF, a putative transcriptional target of MeCP2. However, we recently found that expression and secretion of BDNF are severely impaired in NPG neurons of MeCP2 null mice. In particular, levels of BDNF protein are markedly depressed in mutant NPG neurons compared to wildtype cells, although levels of BDNF mRNA are normal. In addition, mutant cells exhibit abnormally high levels of constitutive BDNF release. As a result, we hypothesize that transynaptic BDNF signaling by visceral sensory neurons in nTS is disrupted by genetic loss of MeCP2. Moreover, recent studies in our laboratory indicate that BDNF can potently modulate the excitability of second order relay neurons in nTS and that this modulation is impaired in MeCP2 null mice. On the basis of these findings we hypothesize that dysregulation of BDNF signaling by NPG neurons contributes to the life-threatening autonomic dysfunctions associated with Rett. However, almost nothing is known about mechanisms of BDNF signaling in nTS in general and the role of MeCP2 in particular. The proposed studies are designed, therefore, to elucidate 1) basic mechanisms of synaptic modulation by BDNF in nTS, using brainstem slice preparations, 2) how loss of MeCP2 function alters BDNF dependent signaling by visceral sensory neurons and synaptic transmission in nTS and 3) the role of BDNF in nTS mediated autonomic reflexes in vivo. In addition, we have recently found that the BDNF deficit in MeCP2 null NPG neurons is reversible in vitro. Therefore, the proposed studies are also designed to develop potential strategies for increasing or restoring normal levels of BDNF expression in MeCP2 null mutants in vivo. By elucidating the roles of BDNF and MeCP2 in autonomic reflex pathways, the proposed research aims to shed light on cellular and molecular mechanisms relevant to understanding and improved management of Rett Syndrome and other disorders of autonomic homeostasis. In particular, it is hoped that defining how MeCP2 disrupts BDNF dependent signaling by visceral sensory neurons will lead to identification of new molecular targets for drug development aimed at improving autonomic function in Rett patients.. [unreadable] [unreadable] [unreadable]